title: Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways.
abstract: To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000 mg/kg body weight twice a day by gavage for 1 and 2 weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500 ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulation of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans.
authors.affiliation: Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Electronic address: anna@med.osaka-cu.ac.jp.
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hagiwara
authors.forename: Norio
authors.initials: N
authors.lastname: Imai
authors.forename: Kasuke
authors.initials: K
authors.lastname: Nagano
authors.forename: Fukumi
authors.initials: F
authors.lastname: Nishimaki
authors.forename: Marcy
authors.initials: M
authors.lastname: Banton
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000393:Air Pollutants / Q000633:toxicity; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D005019:Ethyl Ethers / Q000633:toxicity*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D047492:Peroxisome Proliferator-Activated Receptors / Q000096:biosynthesis*; D000077297:Pregnane X Receptor; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D011987:Receptors, Steroid / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000393:Air Pollutants; D000090702:Constitutive Androstane Receptor; D005019:Ethyl Ethers; D047492:Peroxisome Proliferator-Activated Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C098546:ethyl tert-butyl ether
keywords: 8-OHdG; Apoptosis; Ethyl tertiary-butyl ether; Liver tumors; Mode of action; Oxidative stress